In 1975, a pentapeptide, methionine enkephalin, was reported by Hughes et al. Nature, 258,577(1975). This peptide is found in many areas of the brain where it appears to act as a neurotransmitter of neuromodulator in a central pain suppressant system. The natural peptide binds stereospecifically to partially purified brain opiate receptor cites see, for example, Bradbury et al., Nature 260,793(1976). The natural peptide is also highly active in bioassays for opiate activity but exhibits only weak, fleeting analgesic activity when injected directly into the brain of the rat see for example Belluzi et al., Nature, 260,625(1976).
In order to overcome the lack of in vivo activity, a number of investigators have made numerous modifications in the methionine enkephalin structure, such as substituting the glycine in the 2-position with a D-amino acid, N-methylation of the 1-tyrosine, substituting the 4-phenylalanine with, for example methyl or halo, modifying the C-terminus, etc. to produce enkephalin derivatives of varying properties and potencies.
The present invention provides new enkephalin derivatives and their pharmaceutically acceptable salts which approach the potency of morphine as analgesic agents by both oral and parenteral routes of administration.